The controlled-release of drugs, their targeting to specific sites in the human body and the protection of delicate bioactive agents is desirable for efficient drug delivery. One approach towards achieving these ends involves encapsulating bioactive agents in biocompatible nanoparticle matrices. Control is needed over particle size and size distribution, substructure, crystallinity and thickness of encapsulating shell. Among matrix materials, polymers are not approved by the US-FDA for intravenous or pulmonary applications, because of toxic or allergenic end products from their metabolism, while liposomes are limited by low physical stability and high cost. Lipid nanoparticles, made from physiological lipids, like fatty acids and triglycerides, have shown promise in cellular/tissue targeting, sustained/controlled-release, enhancing solubility of poorly water-soluble drugs, and protection of susceptible therapeutic agents for example: Proteins, peptides, and nucleic acid. Their longer circulation time, in the human system, and higher drug payload have been exploited for treating diseases like cancer and brain disorders.
Preparation of nanoparticle drug matrices from processing of delicate, thermolabile materials, like lipids, including fatty acids and triglycerides, and other materials, including waxes and polymers (polylactides, polycyanoacrylates alginates, chitosan and gelatin), needs to address thermal and shear stress imposed, in addition to complexity (multiple steps, use of high or reduced pressure, cryogenic conditions) and cost. For example, current methods of production of lipid nanoparticles can be categorized as top-down methods such as emulsion based techniques (emulsification-solvent-evaporation; solvent emulsification-diffusion; warm w/o/w microemulsion-based techniques), and high pressure homogenization (hot/cold); and bottom-up methods based on supercritical fluids. Spray-drying and an aerosol reactor method are emerging bottom-up techniques, used at temperature of 100-250° C. to process crystalline drugs, polymers and proteins with high melting points.
Top-down method suffer limitations including imposition of thermal and shear stress, use of surface-active agents, use of high energy intensity and multiple post-processing steps. Emulsion based methods have been used to produce lipid and polymeric nanoparticles containing anti-cancer drugs like Doxorubicin and Podophyllotoxin, while high pressure homogenization has been used to prepare lipid nanoparticles containing protein with high structural stability and stronger internal coherence, such as cyclosporine A and lysozymes. Emulsion based methods often use ultrasonication resulting in high shear, cavitation and collision and large amount of surface-active agents to stabilize dispersion. In lipid-melt based methods, the amount of drug encapsulation is limited by its solubility in the lipid melt and the stability of the nano-emulsion. High-pressure and high shear homogenization are energy intensive. Both types of approaches need multiple post—processing steps including separation, filtration, drying, removal of residual organic solvents and lyophilization which increases manufacturing cost. In addition, there is poor control over properties of nanoparticles leading to phase-changes during shelf-life, drug-expulsion or burst-release kinetics, thermal degradation of the thermolabile active agents, insufficient control over particle size and large surfactant content causing greater cytotoxicity or lower absorption (Bunjes 2010).
Bottom-up methods include those based on super-critical fluid technology [Rapid expansion of supercritical solution (RESS), Gas antisolvent solution (GAS), solution enhanced dispersion with supercritical fluids (SEDS), Supercritical fluid extraction of emulsion (SFEE), particle formation from gas-saturated solutions (PGSS) and Rapid expansion of a supercritical solution into a liquid solvent (RESOLV)], nanoprecipitation, self-assembly of polymeric micelles, spray drying and spray-freeze drying. The use of supercritical fluid technology is limited by the solubility of matrix and drug molecules in supercritical fluids/anti solvents and their denaturing effects on therapeutic macromolecules like proteins and peptides. In addition, there is high manufacturing complexity (maintaining system temperature and pressure above critical point) and production cost (sophisticated instrumentation).
Spray drying, used for generation of micron and sub-micron sized particles requires high temperature, of the order of 150° C. to remove the solvent from the atomized solution drop. In a recently reported study, a commercial spray dryer, equipped with a piezoelectric oscillating element, was employed for production of nanoparticles using a structurally stable protein like bovine serum albumin. Controlling precursor (solute and surfactant concentration) and process (spray mesh size, drying airflow rate and inlet temperature) parameters led to control over size (540-2609 nm diameter) and shape. Protein or peptide particles generated by this techniques often form aggregates; control over particle size is difficult.
An aerosol reactor method to produce micrometer to nanometer sized particles for drug applications uses a heated-wall aerosol flow reactor at temperature of 100-250° C., to process pure crystalline drugs, polymers and drug particles coated with a crystalline excipients. Precursor drugs, excipients and polymers processed by this method had melting temperature in the range of 200-800° C.
In summary, current methods of producing drug-containing nanoparticles include “Top down” and “Bottom-up” methods. Top-down methods are emulsion based techniques and employ high pressure homogenization. The technique suffers from the limitations of high energy intensity and imposition of high thermal and shear stress. Emerging bottom-up methods like spray drying and aerosol reactor method are suitable for production of crystalline drugs, polymers and proteins with high melting points. These methods have limitations in achieving control of target properties like size, crystallinity and control drug-release characteristics.